Tolerizing Effects of Co-stimulation Blockade Rest on Functional Dominance of CD4+CD25+ Regulatory T Cells

Abstract

Clinical tolerance is the net result of regulatory and effector functions. In this article, the authors show that tolerance induction by co-stimulation blockade preferentially works through CD4CD25 regulatory T-cell-mediated suppression that is effectively achieved by selective reduction of the effector T-cell load. Anti-CD86 and anti-CD40L monoclonal antibody treatment during in vitro mixed lymphocyte reaction (MLR) typically results in the induction of a suppressive polyclonal T-cell population. This induced suppressive capacity was found to be dependent on the presence of CD4CD25 T cells at the start of MLR. Using a CFSE-based strategy, the authors show that within the polyclonal T-cell population, the suppressive effect was exerted by a nondividing CD4CD25 T-cell subset. The cells exclusively originated from preexisting CD4CD25 regulatory T cells and proved anergic and highly suppressive on isolation. They carried the CD45RB and CD62L phenotype and expressed GITR. There was no indication of de novo induction of regulatory T cells by co-stimulation blockers. Instead, the authors observed, both in vitro and in vivo, that co-stimulation blockade shifted the ratio between alloreactive effectors and regulatory T cells in favor of the latter. The authors therefore conclude that co-stimulation blockade contributes to functional dominance of regulatory T cells by preventing expansion of alloreactive effector T cells. Tolerance-inducing protocols should ideally facilitate this phenomenon.